A missense mutation in human INSC causes peripheral neuropathy

• Published in: EMBO molecular medicine 2024-05, Vol.16 (5), p.1091-1114
• Main Authors: Yeh, Jui-Yu, Chao, Hua-Chuan, Hong, Cheng-Li, Hung, Yu-Chien, Tzou, Fei-Yang, Hsiao, Cheng-Tsung, Li, Jeng-Lin, Chen, Wen-Jie, Chou, Cheng-Ta, Tsai, Yu-Shuen, Liao, Yi-Chu, Lin, Yu-Chun, Lin, Suewei, Huang, Shu-Yi, Kennerson, Marina, Lee, Yi-Chung, Chan, Chih-Chiang
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Biomedical and Life Sciences; Biomedicine; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - pathology; Charcot–Marie–Tooth Neuropathy Type 2; Disease Models, Animal; Drosophila - genetics; EMBO16; EMBO27; Humans; Inscuteable; Microtubule-Stabilizing Agents; Molecular Medicine; Mutation, Missense; Necrosis; Nuclear Proteins; Peripheral Nervous System Diseases - genetics; Peripheral Nervous System Diseases - pathology; Proprioception; Tubulin - genetics; Tubulin - metabolism
• ISSN: 1757-4684; 1757-4676; 1757-4684
• DOI: 10.1038/s44321-024-00062-w

PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot–Marie-Tooth disease (CMT2) and identified a missense mutation c.209 T > G (p.Met70Arg) in the INSC gene. Modeling the INSC M70R variant in Drosophila , we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSC M70R mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlight a potential therapeutic target for INSC -associated CMT2. Synopsis This study unveils the first discovery of an INSC gene missense mutation causing axonal Charcot-Marie-Tooth disease (CMT) and examines the microtubule-stabilizing role of PAR3/INSC/LGN in the adult peripheral nervous system (PNS). Microtubule-stabilizing agents effectively reverse proprioception defects and necrosis in INSC mutation individuals. Identification of INSC as a potential pathogenic gene in adult-onset peripheral neuropathy. Demonstration of PAR3/INSC/LGN dysfunction leading to proprioceptive defects resembling gait abnormalities in patients with CMT. Requirement of PAR3/INSC/LGN for microtubule stabilization in the adult PNS. Reversal of both morphological and functional defects in a disease model through the use of microtubule-stabilizing agents, presenting a potential therapeutic strategy for peripheral neuropathy. This study unveils the first discovery of an INSC gene missense mutation causing axonal Charcot-Marie-Tooth disease (CMT) and examines the microtubule-stabilizing role of PAR3/INSC/LGN in the adult peripheral nervous system (PNS). Microtubule-stabilizing agents effectively reverse proprioception defects and necrosis in INSC mutation individuals.